Oxidative damage of soft oral tissues may be caused by dental devices in a number of ways. In some situations, this can occur as materials leech out of dental devices and directly cause oxidative damage. Damage can also take place if materials associated with a dental device participate in other reactions that cause or increase oxidative damage, for instance by creating free radicals or other reactive species. Free radicals may also be released by dental devices or produced in the mouth as a result of dental devices, and these are often the cause of oxidative damage to the body. Free radicals and other reactive species are also known to cause oxidative damage to organisms. As this oxidative damage occurs, it may result in inflammation, periodontal disease, and related problems, such as cardiovascular disease or increased susceptibility to formation of cancerous lesions in the mouth.
Periodontal disease often begins with oxidative damage to a few oral cells. The body recognizes and tries to clear away these damaged cells in part through the actions of inflammation pathways. Inflammatory pathways, however, are typically not able to only clean up the damaged cells. Other, healthy cells are damaged in the process, often causing much more harm than the original oxidative damage.
The inflammatory response is triggered by some injurious stimuli such as pathogens, damaged cells, or irritants. In a typical inflammation response, a cascade of biochemical events propagates and matures the inflammation response. Circulating peripheral blood mononuclear cells (PBMCs) such as Leukocytes are important cells in these biochemical cascades. These cells express a range of pathogen-recognition receptors (PRRs) which recognize highly conserved pathogen-associated molecular patterns (PAMPs) present with bacteria, viruses, fungi, mycoplasma, and parasitic protozoa. The largest family of PRRs are the Toll-like receptors (TLRs), the most well-known being TLR4 which is capable of ligating the lipopolysaccharide (LPS) present in the cell wall of many Gram-negative bacteria such as Escherischia coli (E. coli) and Actinobacillus actinomycetemcomitans (Aa). TLR4 is highly expressed by monocytes, marcophages, and neutrophils. The ligation of LPS results in a gene expression program that results in the induction of local inflammation.
Several biochemical molecules may be involved with inflammation or an immune response, and a number of examples follow. Tumor necrosis factor-alpha (TNF-α) is a cytokine involved in systemic inflammation and is used in the initiation of inflammation. C—X—C motif chemokine 5 (CXCL5) is produce during inflammation to stimulates chemotaxis of neutrophils possessing angiogenic properties. Interleukin 8 (IL-8) is a chemokine that is a chemoattractant for certain inflammatory molecules and induces chemotaxis in its target cells. Interleukin 4 (IL-4) induces differentiation of naïve helper T cells to Th2 cells and the stimulation of B-cells. Interleukin 2 (IL-2) is a cytokine that attracts lymphocytes or leukocytes. Interleukin-1 alpha (IL-1α) and Interleukin-1 beta (IL-1β) are cytokines involved in the initial production of inflammation. Granulocyte colony-stimulating factor (G-CSF) is a cytokine that stimulates the bone marrow to produce granulocytes. Granulocyte macrophage colony-stimulating factor (GM-CSF) is a cytokine that stimulates stem cells to produce granulocytes and monocytes. Interferon-gamma (IFN-γ) is a cytokine that increase lysosome activity of macrophages and promotes leukocyte migration. Interleukin 6 (IL-6) is a cytokine involved in acute phase protein synthesis and the production of neutrophils in the bone marrow. Interleukin 10 (IL-10) is an anti-inflammatory cytokine. Interleukin 5 (IL-5) is a cytokine involved with B cell growth and eosinophil granulocyte activation. Interleukin 17 (IL-17) is a cytokine involved in recruiting monocytes and neutrophils to the site of inflammation. Vascular endothelial growth factor (VEGF) is a signal protein involved in vasculogensis. Monocyte chemotactic protein-1 (MCP-1) or chemokine (C-C motif) ligand 2 (CCL2) is involved with recruiting monocytes and other cells to the site of inflammation. Chemokine (C-C motif) ligand 5 (CCL5) is a protein involved in recruiting leukocytes to the site of inflammation and the activation of certain natural-killer (NK) cells. Macrophage inflammatory proteins 1-alpha and beta (MIP-1α and MIP-1β, also known as chemokine (C-C) motif ligand 3 and 4 (CCL3 and CCL4 respectively) are chemokines released by macrophages which activate granulocytes and induce the synthesis and release of other pro-inflammatory cytokines. Interleukin 1 receptor antagonist (IL-1RA) is a protein that binds to the IL-1 receptor, preventing IL-1 from signaling that cell, thus inhibiting inflammation. Thrombopoietin is a glycoprotein that regulates the production of platelets by the bone marrow. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that plays a key role in regulating the immune response to infection, particularly by controlling many genes involved. IκB-α is a protein that functions to inhibit the NF-κB transcription factor.
Current treatments for periodontal disease involve surgery in the local area or antibiotics if the periodontal disease has progressed far enough to allow infection to set in. These treatments do not address the underlying systemic nature of periodontal disease and instead merely address very specific and local problems. Further, they have limited or no ability to cause regrowth and healing of the diseased tissue. Other problems resulting from oxidative damage of soft oral tissues similarly do not have effective treatments. Accordingly, a need exists for effective methods to treat periodontal disease and other soft oral tissue diseases resulting from oxidative damage or to prevent such disease or damage all together.
Antioxidants are known to protect organisms, such as humans, from oxidative damage, but their effective administration is a problem. For example, antioxidants ingested in food or as a pill have a limited effect on periodontal disease because the uptake and management of antioxidants is tightly regulated by body mechanisms such that antioxidants are distributed to all body parts, resulting in only a minimal portion of the ingested amount reaching the soft oral tissues and thus limiting the antioxidant effect in that tissue. Similarly, previous antioxidant compositions have been developed for use in specific areas, such as the skin, but these compositions are not suitable for use on soft oral tissue due to the many differences between skin and soft oral tissue. For example, commonly used skin antioxidant compositions are formulated at a pH far too low for use in the oral environment, and will demineralize tooth enamel. There are other issues of compatibility with formulations intended for use on the skin, which frequently contain oils, lipids and detergents that are inappropriate or ineffective in the moist environment of the mouth.
Accordingly, a need exists for antioxidant compositions able to topically treat or prevent soft oral tissue diseases resulting from oxidative damage caused by dental devices.